Combination of an inhibitor of glucose metabolism and BH3 mimetic for increased efficacy in the treatment of multiple myeloma.
- Activates cell death pathways through independent molecular mechanisms, resulting in enhanced effect with combination therapy.
- Repurposed use of FDA-approved therapies to expand indications in oncology.
Multiple myeloma (MM) is a plasma cell malignancy that is largely incurable and claims over 11,000 lives annually in the US alone. Despite use of new medicines, treatment options and stem cell replacement, MM remains an aggressive killer largely due to the development of drug resistance. Resistance is mediated in part by ineffective engagement of the proteins involved in the execution of apoptosis. Co-therapies targeting distinct proteins involved in the regulation of apoptosis may reduce the development of resistance observed in current MM therapies. Enhanced activation and/or alteration of pro-apoptotic regulators can improve efficacy of existing therapeutic strategies in MM.
BH3 mimetics have been developed to target pro-survival BCL-2 proteins allowing the sequestered pro-apoptotic BCL-2 members to be released to trigger cell death. Multiple myeloma (MM) is heavily dependent on various nutrients for survival and removal of glucose or glutamine can result in apoptosis. Researchers at Emory have shown that inhibiting glucose or glutamine metabolism further sensitizes MM to BH3 mimetics. The researchers have also identified a combination of glucose inhibitor and BH3 mimetic with which co-treatment of cancer cell lines and MM cells isolated from patients increased the amount of cell death in culture. Co-administration of glucose or glutamine inhibitors and BH3 mimetics may be a potent therapeutic strategy against multiple myeloma.
Proof of concept in vitro experiments have been conducted showing enhanced cell death with co-administration.
Publication: Shanmugam M et al. Oncogene. 2015 Dec 7.